Understanding the genetic basis of disease and drug response has the potential to improve therapy and enable early intervention or prevention. However, the main genetic factors remain only partially understood, even while the number of candidate genes is rapidly growing, as a result of genome-wide association studies. Polymorphisms that alter protein sequence are readily detectable, but growing evidence indicates that regulatory polymorphisms are more prevalent, affecting mRNA expression, processing, and translation. Yet, regulatory variants are difficult to detect, and moreover, their functions depend on tissue context and environment, so that a majority remains hidden. The central goal of this proposal is a comprehensive discovery of regulatory polymorphisms in ~200 pharmacotherapeutic candidate genes, followed by molecular studies to understand the underlying mechanisms, and clinical evaluation in drug therapy - the first such systematic study in pharmacogenomics. We have developed a comprehensive approach to the discovery of regulatory polymorphisms, measuring allelic mRNA expression, processing, and translation in relevant human target tissues. This approach has already revealed unexpected and frequent regulatory variants in genes encoding drug metabolizing enzymes and receptors, gaining a powerful link between genotype of proven function and clinical outcomes (examples: DRD2, TPH2, ACE, VKORC1, CETP, and CYP3A4). These results support a critical role for regulatory polymorphisms in drug response. The main focus in this proposal is on drug metabolism genes and impact on pharmacokinetics-pharmacodynamics. In addition, building on other ongoing studies, the project includes genes encoding drug receptors/targets, with focus on CNS disorders (schizophrenia) and cardiovascular diseases (myocardial infarction, lipid metabolism), to be tested in association studies led by experienced clinical scientists. Driven by the motto 'from clinic to laboratory', new genetic studies have been initiated on estrogen and glucocorticoid receptors, the latter to be tested in glucocorticoid-resistant nephrotic syndrome in children. The long-term goal is to develop and validate genetic biomarker panels for optimizing personalized drug therapy.